Fused thiazines

ABSTRACT

NOVEL THIAZINE COMPOUNDS OF THE FOLLOWING FORMULAE ARE DISCLOSED   2-(R4-N(-R5)-),4,5-(-(CH2)N-)(-R1),6-R2,6-R3-6H-1,3-   THIAZINE,   2-(R7-N=),3-R6,4,5-(-(CH2)N-)(-R1),6-R2,6-R3-6H-1,3-   THIAZINE   THESE COMPOUNDS HAVE ANALGETIC AND ANTI-INFLAMMATORY ACTIVITY. PHARMACEUTICAL COMPOSITIONS CONTAINING THESE THIAZINE COMPOUNDS ARE ALSO DISCLOSED AS WELL AS PROCESSES FOR THE PRODUCTION OF SUCH COMPOUNDS.

United States Patent ifice Patented June 22, 1971 11.5. C1. 260-243 8 Claims ABSTRACT OF THE DISCLOSURE Novel thiazine compounds of the following formulae are disclosed processes for the production of such compounds.

This invention relates to novel heterocyclic compounds having biological activity, for example analgetic and antiinflammatory activity, and to compositions containing the same.

The present invention provides thiazine derivatives of general Formulae I and II in which n has the value 3 or 4, R represents a hydrogen atom or one or more alkyl radicals; R and R which may be the same or different represent straight or branched chain alkyl radicals containing from one to six carbon atoms, or R and R togther may form a divalent alkylene chain (CH where m has the value 4 or 5 and the ring so formed may be substituted by one or more alkyl radicals; R and R which may be the same or different and represent hydrogen atoms or straight or branched chain alkyl radicals containing from one to six carbon atoms, or aryl, acyl, aroyl or alkoxy-carbonyl radicals or together with the adjacent nitrogen atom may form a heterocyclic ring, optionally containing other hetero atoms; R and R which may be the same or different represent straight or branched chain alkyl radicals containing from one to six carbon atoms, or in which R and R may together form a divalent alkylene radical (CH where p has the value 2 or 3 and R has the meaning given above and physiologically acceptable salts thereof.

Preferred compounds according to the invention are those the preparation of which is described in the examples.

The compounds of the present invention have been found to have useful biological activity, for example analgetic and anti-inflammatory activity. Such compounds may be formulated for use in human or veterinary medicine, for therapeutic purposes.

For example the compounds of Formula III is nearly as active (ED approximately 10 mg./kg.) as indomethacin (ED 7.5 mg./kg.) in protecting mice from the erythema produced by ultraviolet radiation, As an antagonist of the inflammation arising from the injection of carageenin in the hind foot of the rat compound III has an ED value of 27.5 mg/kg. (indomethacin 9.6 mg./ kg). Compound III has marked advantages over indomethacin in its lack of ulceration of the gastro intestinal tract and its failure to cause retention of salt and water in the body.

N J N'Me: s

III

The invention therefore includes within its scope pharmaceutical compositions comprising as active ingredients thiazine derivatives of general Formula I and II, or physiologically acceptable salts thereof. Such compositions may be presented for use in a conventional manner with the aid of carriers or excepients and formulatory agents as required, and with or without supplementary medicinal agents.

The compositions may include for instance solid and liquid preparations for oral use, suppositories and injections. Oral administration is most convenient in the form of tablets which may be prepared according to conventional methods, and may be coated if required. Injections may be formulated with the aid of physiologically acceptable carriers and agents as solutions, suspensions, or as dry products for reconstitution before use. The effective daily dose of the active ingredient may be varied as required but will in general be within the range of 50 to 500 mg. depending on the age, weight, and condition of the patient.

The thiazine derivatives of Formulae I and II may be prepared by condensing a cycloalkanone or alkylidene cycloalkanone with an appropriate thiourea derivative and accordingly the invention provides such process.

Thus for example, the compounds of Formula I may be prepared by the condensation of a cycloalkanone or alkylidene cycloalkanone including cycloalkylidene cycloalkanone with thiourea itself, or with a monosubstituted or 1,1-disubstituted thiourea.

O f H Rl- I (C H3) n+1 (CH2)n during the condensation reaction due to the strongly acidic conditions. The compounds of Formulae I in which R; and/ or R are acyl, aroyl, or alkoxycarbonyl may be prepared from the corresponding compounds in which R and/or R are hydrogen by conventional methods, for example by reaction with an acyl or aroyl halide, or with an alkyl chloroformate.

In the above formulae R R R R R and n have the meanings given above. The value of n+1 in the carboxylic ring of the spirocyclic structure is equal to m as given above.

The compounds of Formula II may be prepared by the condensation of the cycloalkanone or cycloalkylidene cycloalkanone with a 1,3-disubstituted thiourea.

EXAMPLE 1 2-amino-4,5,6,7-tetrahydro-spiro [cyclopenta(d) 3,1- thiazine-4,1-cyclopentane]maleate Cyclopentanone (84 ml.), thiourea (7.4 g.) and cone. hydrochloric acid ml.) were heated at 80 C. for 20 hours. The mixture was diluted with water (200 ml.) and extracted with ether (2X 200 ml.). The aqueous phase was made alkaline and extracted with ether (3 X 150 ml.) Evaporation of the ethereal extract gave an oil which yielded a crystalline maleate (10 g., M.P. 166) from ethyl acetate.

EXAMPLE 2 2-dimethylamino-5,6,7,S-tetrahydro spiro [(4H)-3,1- benzothiazine-4,1'-cyclohexane] Cyclohexanone (300 ml.), 1,1-dimethylthiourea (52 g.) and cone. hydrochloric acid (100 ml.) were heated at reflux for 1.5 hours. The mixture was cooled and extracted with ether. The aqueous phase was basified and extracted with ether (X 300 ml. These extracts were washed, dried and evaporated and the residual oil which solidified on cooling was crystallised from 80% aqueous ethanol to give the thiazine (82 g.), M.P. 745.

The base (592 g.) in benzene (1200 ml.) Was treated with one equivalent of 2 N ethanolic hydrogen chloride and the solvents were then removed. Crystallisation of the residue from benZene-isopropyl acetate gave the hydrochloride (612.5 g.), M.P. 182.

EXAMPLE 3 2-acetamido-5,6,7,8-tetrahydro spiro [(4H) 3,1- benzothiazine-4,1'-cyclohexane] 2-amino-5,6,7,8-tetrahydro spiro [(4H) 3,1-benzothiazine-4,1'-cyclohexane]hydrochloride (5.5 g.) in chloroform (50 ml.) containing triethylamine (6 ml.) was treated at 0 with acetyl chloride (1.95 ml.). After 24 hours at room temperature the solution was evaporated and the residue treated with water and ether. Evaporation of the ethereal extracts and crystallisation of the residue from ethyl acetate gave the thiazine (4.6 g.), M.P. 174.

The compounds shown in Table 1 were prepared by methods similar to those used in the above examples.

2-dimethylamino-5,6,7,8-tetrahydro-4,4,7-trimethyl- (4H) -3 l-benzothiazine Pulegone (15 ml.) and 1,1-dimethylthiourea (4 g.) were allowed to stand at 30 for 24 hours in saturated ethanolic hydrogen chloride ml.). The solvent was removed and the residue taken up in 2 N hydrochloric acid (50 ml.) and extracted with ether. The aqueous phase was made alkaline to pH 12 and extracted with ether (3 100 ml.). These extracts after being washed, dried and evaporated gave a yellow oil which was crystallised from ethyl acetate, as the maleate salt, M.P. 130.

The following compounds were prepared by a similar method.

EXAMPLE 23 2 amino 5,6,7,8-tetrahydro-4,4,7-trin1ethyl-(4H)-3,lbenzothiazine, M.P. 102.

EXAMPLE 24 2 ethylamino-5,6,7,8-tetrahydro-4,4,7-trimethyl-(4H)- 3,1-benzothiazine, M.P. 92-3.

EXAMPLE 25 2 amino 4-(l-ethylpropyl)-5,6,7,8-tetrahydro-(4H)- 3,1-benzothiazine, hydrochloride, M.P. 136.

EXAMPLE 26 2,3,7,8,9,lO-hexahydrospiro 1H,6H)-pyrimido[ 1,2-a] 3 ,1-benzothiazine-6,l'-cyclohexane] Cyclohexanone (49 ml.) tetrahydropyrimidine-2(1H)- thione (5.8 g.), and cone. hydrochloric acid (10 ml.) were heated at reflux for 2 hours. The mixture was cooled, diluted with water (40 ml.), and extracted with ether. The aqueous phase was made alkaline and extracted with ether (3 100 ml.). Evaporation of this ethereal extract gave an oil that crystallised from cyclohexane to yield the thiazine (10 g.), M.P. hydrochloride, M.P. 235

The following compounds were similarly prepared.

EXAMPLE 27 1,2,6,7,8,9 hexahydrospiro[(5H) imidazo(1,2-a)3,1- benzothiazine-S,1-cyclohexane], M.P.

EXAMPLE 28 l-ethyl 2 ethylimino-l,2,6,7,8-hexahydrospiro[(4H) 3 ,1-benzothiazine-4,1'-cyclohexane] hydro chloride, M.P. 173-175 EXAMPLE 29 1,2,5,6,7,8 hexahydro 1 methyl-2-methyliminospiro 4H) 3 l-benzothiazine-4,1'-cyclohexane] hydrochloride, M.P. 176179.

EXAMPLE 30 Tablets 12.5 kg. of 2-dimethylamino 5,6,7,8 tetrahydrospiro [(4H)-3,l-benzothiazine-4,l'-cyclohexane], and 5 kg. of calcium sulphate were mixed together. Suificient 1% aqueous solution of sodium carboxymethyl cellulose was added and the mixing continued until a damp cohesive mass was formed. The damp mass was granulated by passing through a No. 12 mesh sieve and the granules were then dried at 50 C. After drying the dried granules were passed through a No. 16 mesh screen and mixed with 3.75 kg. of maize starch and 125 g. of a magnesium stearate. The lubricated granules were compressed by means of a suitable tableting machine using A punches and dies to produce 50,- 000 tablets each weighing about 430 mg. and containing 250 mg. of 2-dimethylamino-5,6,7,S-tetrahydrospiro[ (4H) 3, l-benzothiazine-4, l-cyclohexane] \EXAMPLE 31 Capsules We claim: 1. A thiazine derivative of Formulae I and II N N i\/ \W (CH2)B S CDJL/I R R3 Rg R3 I II in which n has the value 3 or 4; R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms; R and R which may be the same or dilferent, represent straight or branched chain alkyl radical containing from one to six carbon atoms, or R and R together may form a divalent alkylene chain (CH where in has the value 4 or 5 and the ring so formed may be substituted by lower alkyl radicals; R and R which may be the same or different and represent hydrogen atoms or straight or branched chain alkyl radicals containing from one to six carbon atoms, or phenyl, acetyl, benzoyl or lower alkoxy-carbonyl radicals or together with the adjacent nitrogen atom may form a morpholino or piperidino group; R and R, which may be the same or different and represent straight or branched chain alkyl radicals containing from one to six carbon atoms, or in which R and R may together form a divalent alkylene radical (CH where p has the value 2 or 3 and physiologically acceptable salts thereof.

2. A compound of claim 1 which is 2-dimethylamino- 5,6,7,8-tetrahydrospiro[(4H)3,1-benzothiazine 4,1 cycyohexane].

3. A compound of claim 1 which is 5,6,7,8-tetrahydro- 4,6-dimethyl 2 methylaminospir[(4I-I)3,1-benzothiazine-4, 1-cyclohexane] 4. A compound of claim 1 which is 2-amino-4(l-ethylpropyl) ,6,7,8-tetrahydro- (4H 3, l-benzothiazine, hydrochloride.

5. A compound of claim 1 which is 2,3,7,8,9,l0-hexahydrospiro[(1H,6H)-pyrimido[1,2-a] 3,1 benZ0thiaZine 6,1-cyclohexane.

6. A compound of claim 1 which is 5,6,7,8-tetrahydro- 2-piperidinespiro[(4H)3,1-benzothiazine 4,1 cyclohexane].

7. A process for the preparation of a thiazine compound of the following formulae in which n has the value 3 or 4; R represents a hydrogen atom or an alkyl radical containing from 1 to 4 carbon atoms; R and R which may be the same or different, represent straight or branched chain alkyl radicals containing from one to six carbon atoms or R and R together may form a divalent alkylene chain (CH where m has the value 4 or 5 and the .ring so formed may be substituted by lower alkyl radicals; R and R which may be the same or difierent and represent hydrogen atoms or straight or branched chain alkyl radicals containing from one to six carbon atoms or phenyl, acetyl, benzoyl or lower alkoxy-carbonyl radicals or together with the adjacent nitrogen atom may form a heterocyclic ring, optionally containing an oxygen atom; R and R; which may be the same or different and represent straight or branched chain alkyl radicals containing from one to six carbon atoms, or in which R and R may together form a divalent alkylene radical (CH where p has the value 2 or 3 and physiologically acceptable salts thereof, which comprises reacting a cycloalkanone of the formula (arm...

or an cycloalkylidene cycloalkanone of the formula 1 CH2) n+1 or a alkylidene cycloalkanone of the formula (in which formula R R R and n have the meanings given above) with thiourea, a monosubstituted or 1,1-disubstituted urea for the production of compounds of Formula I, or for the production of compounds of Formula II with a 1.3-disubstituted urea, in both cases with subsequent conversion, if desired of the groups R; and R when hydrogen atoms into acyl, aroyl or alkoxy carbonyl groups by conventional methods, the compounds being isolated as the acid addition salts if desired.

8. A process as claimed in claim 7 in which the reaction takes place in the presence of an acid catalyst.

References Cited UNITED STATES PATENTS 3,417,085 12/1968 Kuch et al 260243 3,502,666 3/1970 Kuch et al 260-243 JOHN M. FORD, Primary Examiner US. Cl. X.R. 424-246 

